tbuckley/cabot-search huggingface dataset:
Immunogenicity and disease control induced by a multineoantigen vaccine (ADXS-503) in patients with metastatic non–small cell lung cancer who have progressed on pembrolizumab.
Authors: Aaron E. Lisberg, Jonathan W. Goldman, Balazs Halmos, Gregory James Gerstner, Neil Morganstein, Charles Michael Farber, Kyoung A Viola Lee, Lydia ML Holtgrewe, Casey Codd, Angelina Bisconte, Theodore Foss, Surya Vangala, Megan Parsi, Andres A. Gutierrez, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2022)

9042 Background: The administration of a lung cancer-specific immunotherapy with 22 tumor-associated antigens (ADXS-503, A503), has been evaluated as an add-on therapy for patients (pts) with metastatic non-small-cell lung cancer (NSCLC) who have progressed on pembrolizumab (pembro) as last therapy [Haigentz M et al. ASCO 2021]. The present study explores the immunogenicity and potential reversal of immune resistance with A503 when added-on to pembro at the time of progressive disease (PD). Methods: A phase 2 study of A503 + pembro is being conducted in pts with metastatic squamous or non-squamous NSCLC. In Part B of the study, A503 was added-on to pembro within 12 weeks after the first scan showing disease progression following pembro therapy (per RECIST criteria v1.1). Both A503 (1x10 8 CFU) and pembro (200 mg) were infused by IV every 3 weeks until disease progression or dose-limiting toxicity. Immunogenicity assays included serum cytokine and chemokine levels; flow cytometry; and in-vitro stimulation FluoroSpot assay with 4 different antigen-pools represented in A503 [i.e., hot spot mutations, heteroclitic/wild-type tumor-associated antigens and other antigens not included in the A503 construct (antigen spreading)]. Results: A total of 14 pts have been treated in Part B, of which 13 are clinically evaluable and up to 11 have immune assessments. Combination therapy was well tolerated with transient increased secretion of cytokines for several hours after infusion of A503 consistent with the expected immune activation and transient ‘flu-like’ syndrome. The objective response rate (16%) and disease control rate (46%) were encouraging with 2 partial responses (PR), 4 stable diseases (SD) and 7 pts with PD. Pts with disease control, in particular, generated CD8+ T cells reactive to neoantigens in 1 or more of the 4 antigen pools tested in FluoroSpot. Also, activation of NK cells and of cytotoxic- and memory-CD8+ T cells was mainly observed in pts with PR or SD, but not in those with PD, as shown in the table. Conclusions: Adding A503 to pembro after PD appears to induce innate and adaptive immune responses that may restore or enhance sensitivity to checkpoint inhibitors in pts with clinical benefit. Clinical trial information: NCT03847519. [Table: see text]
DDEL-07. A Phase I study examining the feasibility of intermittent convection-enhanced delivery (CED) of MTX110 for the treatment of children with newly diagnosed diffuse midline gliomas (DMGs)
Authors: Stergios Zacharoulis, Luca Szalontay, Travis CreveCoeur, Justin Neira, Dominique Higgins, Zachary Englander, Eleonora Spinazzi, Chankrit Sethi, Peter Canoll, James Garvin, Rebecca Zylber, Steve Damment, Dmitry Zamoryakhin, Alexis Maddocks, Neil Feldstein, Jeffrey Bruce
Journal: Neuro-Oncology (2022)

Abstract Histone deacetylase inhibitors have been found preclinically to be among the most active agents against DMGs, however, they are clinically ineffective with systemic delivery due to blood brain barrier limitations and toxicity. Using a repurposed device (implantable subcutaneous pump connected with a catheter directly implanted into the pons/thalamus) we are performing a phase I, standard 3 + 3 dose escalation study to investigate the safety and feasibility of repeated infusions of MTX110 (Midatech Pharma), a water-soluble formulation of panobinostat, via CED. Eligible patents are between 3 and 18 years of age with newly diagnosed DMG following radiation therapy, without hemorrhage or cyst in the tumor, and having intact organ function. Following tumor biopsy and device implantation, patients receive two 48-hour-infusion pulses 7 days apart of MTX110 (30, 60, or 90 mM). The infusion pump is prefilled with MTX110 (and gadolinium for co-infusion to serve as a surrogate for drug distribution) and administered using the wireless N’Vision clinical programmer at a rate of 0.2 mL/hr. Seven patients (30 mM group, n=3 and 60 mM group, n=4) have been treated with the MTX110 infusate. All but one patient had adequate tumor coverage as measured by co-infused gadolinium on MRI. One patient suffered a severe adverse event related to the infusion and tumor anatomy. Four patients had Grade 2 transient neurological deficits related to biopsy (n=1) and the infusion (n=3). In a follow up period of 12-22 months from diagnosis, progression free survival ranges from 8 to 20 months. With one objective response, 3 patients remain alive (2 without progression, both at 12 months, and 1 with progressive disease, at 22 months post diagnosis). Three patients are expected to be treated at 90 mM level. Using MTX110, we demonstrated the safety and feasibility of repeated drug infusion by CED in DMG patients.
Cardiovascular adverse events-related to GnRH agonists and GnRH antagonists: Analysis of real-life data from Eudra-Vigilance database
Authors: C. De Nunzio, A.F.M. Cicione, F. Di Giacomo, G. Disabato, A. Nacchia, C. Gravina, O.A. Voglino, A. Franco, R. Lombardo, L. Rovesti, V. Baldassarri, S. D'Annunzio, B. Turchi, G. Gallo, J. Stira, A. Guercio, G. Guarnotta, A. Tubaro
Journal: European Urology (2022)
IMG-13. Role of diffusion weighted imaging of spine in pediatric brain tumors showing diffusion restriction and CSF metastases
Authors: Arpita Sahu, Archya Dasgupta, Shradha Lad, Abhishek Chatterji, Ayushi Jain, Epari Sridhar, Tejpal Gupta
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Early detection of leptomeningeal metastases (LM) with paediatric brain tumors cases can change the prognosis as well as course of treatment. Conventional MR imaging and CSF (cerebrospinal fluid) analysis plays a vital role in detection of metastases, however, due to certain limitations these can be missed. In our study, diffusion weighed imaging (DWI) of spine was able to bridge this gap and increased the detection rate in MRI equivocal cases in which CSF study was negative. AIMS: To evaluate the incremental value of DWI over the conventional sequences in detection of LM. MATERIALS &amp; METHODS: Paediatric patients with primary brain tumors known to show restriction and propensity for CSF metastasis underwent MRI on 1.5T Philip’s machine. CSF analysis and radiological follow up were used to confirm the diagnosis. RESULTS: Of the 26 patients proven to have LM, linear leptomeningeal metastases (LLP) were seen in 7 patients and nodular leptomeningeal metastases (NLM) were seen in 6 patients and both were seen in 13 patients. Of the 20 patients with LLM, 18 were detected on contrast; however, these were not detected on T2W and DWI except one patient with thick LLP. In 19 patients with NLM, a total of 84 lesions were detected. All were appreciated on contrast with additional 6 lesions which were false positive (FP). Total 96 lesions were detected on T2W, of which 80 were true positive and 16 were FP. About 80 lesions were detected on DWI. Thus, on contrast sequence FP were 6 while on T2W 16 were FP. DISCUSSION: DWI showed a lower FP rate than conventional sequences. CONCLUSION: Contrast sequence remains most reliable sequence for the detection of LM. However, DWI is useful in equivocal cases. The role of DWI in Group 3 and 4 Medulloblastoma with non-enhancing metastases needs to be further explored.
A study of neo-adjuvant and adjuvant ofra-vec (VB-111) for treatment of surgically accessible recurrent GBM.
Authors: Patrick Y. Wen, Andrew J. Brenner, Nicholas A. Butowski, Tamar Rachmilewitz Minei, Dror Harats, Timothy Francis Cloughesy
Journal: Journal of Clinical Oncology (2022)

TPS2075 Background: Ofranergene obadenovec (ofra-vec, VB-111) is an anti-cancer gene based immune activator and targeted vascular disruptor. The dual mechanism of action triggers a broad antiangiogenic effect and induces of a tumor directed immune response. A previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with ofra-vec monotherapy, that was continued after progression in combination with bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of ofra-vec will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses. Methods: Study NCT04406272 is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy ofra-vec in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous ofra-vec prior to resection, and ofra-vec every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and ofra-vec every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care; however, ofra-vec will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is to evaluate the influence of neoadjuvant ofra-vec on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, 6mPFS and OS. Study is open for enrolment. Clinical trial information: NCT04406272.
OTHR-02. Ways to lower anxiety and influence pain perception by reducing stress hormones and impacting the neurochemicals of patients
Authors: Jennifer Fernjack
Journal: Neuro-Oncology (2022)

Abstract In this session, you will learn how things in everyday life such as music, laughter, gratitude, acts of kindness and pets can take the edge off a patient’s experience by affecting them physically. The speaker can describe these things first hand by sharing what she experienced through her meningioma brain tumor scare and the corresponding radiation treatments. She can also speak to the benefits of “salient stimulus,” whereby patients who listen to music that is relevant to them during radiation treatments are more apt to be less stressed than other patients because the songs that have meaning can increase dopamine levels. The same can be said for people with dementia who listen to their favorite songs. The balance and stride length of people who have Parkinson’s disease can improve as well when they dance to music that has meaning for them and dopamine levels are influenced along the way. Promoting such things in a hospital setting can benefit the underlying patient and their caregivers, e.g., their families and the people who help them at the hospital. The hospital itself has the potential to benefit too through lower turn over rates with staff and lower sedation rates of patients. Great reminder that even though we can’t control the quantity of life, we can still influence the quality of it, regardless of who you are or where you’re from.
Drinking Water Disinfection Byproducts, Ingested Nitrate, and Risk of Endometrial Cancer in Postmenopausal Women
Authors: Danielle N. Medgyesi, Britton Trabert, Joshua Sampson, Peter J. Weyer, Anna Prizment, Jared A. Fisher, Laura E. Beane Freeman, Mary H. Ward, Rena R. Jones
Journal: Environmental Health Perspectives (2022)

Background: Disinfection byproducts (DBPs) and N-nitroso compounds (NOC), formed endogenously after nitrate ingestion, are suspected endometrial carcinogens, but epidemiological studies are limited. Objectives: We investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort. Methods: Among postmenopausal women in the Iowa Women's Health Study cohort, we evaluated two major classes of DBPs, total trihalomethanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen (NO3-N) in public water supplies (PWS) in relation to incident primary endometrial cancer (1986–2014). For women using their PWS >10y at enrollment (n=10,501; cases=261), we computed historical averages of annual concentrations; exposures were categorized into quantiles and when possible ≥95th percentile. We also computed years of PWS use above one-half the U.S. maximum contaminant level (>½ MCL; 40μg/L TTHM; 30μg/L HAA5; 5mg/L NO3-N). Dietary nitrate/nitrite intakes were estimated from a food frequency questionnaire. We estimated hazard ratios (HR) and 95% confidence intervals (CI) via Cox models adjusted for age, endometrial cancer risk factors [e.g., body mass index, hormone replacement therapy (HRT)], and mutually adjusted for DBPs or NO3-N. We evaluated associations for low-grade (cases=99) vs. high-grade (cases=114) type I tumors. We assessed interactions between exposures and endometrial cancer risk factors and dietary factors influencing NOC formation. Results: Higher average concentrations of DBPs (95th percentile: TTHM ≥93μg/L, HAA5 ≥49μg/L) were associated with endometrial cancer risk (TTHM: HR95vsQ1=2.19, 95% CI: 1.41, 3.40; HAA5: HR95vsQ1=1.84, 95% CI: 1.19, 2.83; ptrend<0.01). Associations were similarly observed for women greater than median years of PWS use with levels >½ MCL, in comparison with zero years (TTHM: HR36+vs0y=1.61, 95% CI: 1.18, 2.21; HAA5: HR38+vs0y=1.85, 95% CI: 1.31, 2.62). Associations with DBPs appeared stronger for low-grade tumors (TTHM: HRQ4vsQ1=2.12, 95% CI: 1.17, 3.83; p-trend=0.008) than for high-grade tumors (TTHM: HRQ4vsQ1=1.40, 95% CI: 0.80, 2.44; p-trend=0.339), but differences were not statistically significant (p-heterogeneity=0.43). Associations with TTHM were stronger among ever HRT users than non-HRT users (p-interaction<0.01). We observed no associations with NO3-N in drinking water or diet. Discussion: We report novel associations between the highest DBP levels and endometrial cancer for our Iowa cohort that warrant future evaluation. https://doi.org/10.1289/EHP10207
IMG-09. Characterisation of a panel of<i>in vivo</i> models of paediatric-type diffuse high-grade glioma (PDHGG) using magnetic resonance imaging
Authors: Jessica Boult, Diana Carvalho, Ketty Kessler, Maria Vinci, Elisabet Fernandez, Lynn Bjerke, Mariama Fofana, Valeria Molinari, Angel Carcaboso, Chris Jones, Simon Robinson
Journal: Neuro-Oncology (2022)

Abstract Novel therapies for paediatric-type diffuse high-grade glioma (PDHGG) are urgently required. Orthotopic models using patient-derived material are invaluable tools in preclinical drug development as they retain key genetic/epigenetic features, eg. histone H3G34 or H3K27 alterations. Their evaluation in situ is vital and requires sensitive imaging techniques such as MRI. 12 diffuse hemispheric glioma (DHG; 2 DHG-G34) and 21 diffuse midline glioma (DMG; 17 DMG-K27M) tumours have been characterised using MRI following site-specific orthotopic implantation of patient-derived cells directly from tumour material or after minimal expansion as stem cell cultures. Of the 62 models implanted; 3 DHG and 10 DMG samples were not tumourigenic and 13 DHG/3 DMG models are currently under MRI surveillance. Tumours identified on T2-weighted (T2w)-images varied from a diffuse hyperintense signal to well-defined high contrast masses. Tumour growth in 5 DMG models was too diffuse for longitudinal monitoring with T2w-MRI. Once established, diffusion-weighted, T1/T2 mapping and contrast-enhanced MRI were used to further assess tumour phenotype. Quantitative data from 15 DMG models demonstrated higher water diffusivity and T2 than 10 DHG tumours, which suggests less tightly packed tumour cells but may also reflect the closer proximity of tumours growing in the thalamus/pons/cerebellum to the ventricular system. Lack of contrast-agent enhancement in 11 DMG and 6/10 DHG models indicated an intact blood-brain barrier (BBB), with heterogeneous disruption observed in 4 DHGs; H3-G34 had no bearing on BBB integrity. Upon serial re-implantation survival was shortened in 3/4 DHG and 2/6 DMG models, while quantitative MRI parameters remained similar. Likewise, when 2 DHG and 2 DMG models grown in 2D/3D in vitro were implanted in parallel, poorer survival/improved penetrance was associated with 3D-cultured cells with no difference in imaging phenotype. The study highlights the potential of non-invasive MRI to accurately evaluate the efficacy of novel therapeutics in these PDHGG models.
Recommendations for using Big Data in Prostate Cancer: The experience from the PIONEER Watchful Waiting Study-a-thon
Authors: K. Beyer, E.J. Smith, G. Gandaglia, S. Remmers, A. Golozar, N. Zounemat Kermani, R. Herrera, R. Snijder, S. Evans, A. Achtman, C. Steinbeisser, P-P.M. Willemse, M.I. Omar, B. De Meulder, C. Reich, K. Van Bochove, M.J. Roobol, M. Van Hemelrijck, A. Bjartell, A. Asiimwe, J. N'Dow
Journal: European Urology (2022)
Disparities in speed to BMT consult and allograft in 279 adults with AML.
Authors: Warren Benjamin Fingrut, Boglarka Gyurkocza, Eric Davis, Jessica Flynn, Andromachi Scaradavou, Stephanie Chinapen, Kristine Naputo, Sean Quach, Christina Cho, Sergio Giralt, Esperanza Bouza Papadopoulos, Miguel-Angel Perales, Brian C. Shaffer, Ioannis Politikos, Juliet Naomi Barker
Journal: Journal of Clinical Oncology (2022)

6523 Background: Whether patient (pt) ancestry impacts the time to BMT is not established. Methods: We hypothesized that non-European (non-EURO) ancestry AML pts are at increased risk of delayed time to transplant. Thus, we analyzed time to allograft (Allo) by ancestry defining delayed (late) times as: Allo Indication to BMT Consult (Ind. – Consult) &gt; 90 days, Consult – BMT &gt; 120 days &amp; Allo Indication to BMT (Ind. - BMT) &gt; 180 days. We studied pts &lt; 70 yrs transplanted 1/2016-7/2021. Results: In 279 AML pts (median 56 yrs, range 19-69), BMT indication was date of diagnosis if ELN 2017 intermediate/ high risk &amp;/or high risk mutations &amp;/or sAML in 261 (94%) pts, or date of refractory/ relapsed disease in 18 (6%) pts. European (EURO) pts (n = 195, 70%; median 60 yrs) were older than non-EURO pts (n = 84, 30%; median 49 yrs), p &lt;.001. Most HLA-matched sibling (SIB) (27/33, 82%) &amp; 8/8 HLA-matched unrelated donor (mURD, 113/138, 82%) recipients were EURO; more non-EURO pts received HLA-disparate grafts [cord blood (CB)/ haplo/ mmURD]: 48/84 (57%) vs 55/195 (28%), p &lt;.001. Overall, median (range) times for BMT Ind. - Consult, Consult - BMT, &amp; Ind. - BMT were 45 (1-1127), 86 (13-1628), &amp; 135 (23-1683) days. 15% of pts had late BMT Ind. - Consult, 27% late Consult – BMT, &amp; 28% late Ind. - BMT. In multivariate analysis (significant variables in Table), more older pts had late Consult - BMT &amp; Ind. - BMT; more non-EURO pts had late Ind. - Consult, Consult - BMT &amp; Ind. – BMT; &amp; despite mostly being non-EURO (35/67, 52%), fewer CB recipients had late Consult - BMT. In mURD pts, BMT Ind. - BMT time was delayed in non-EURO (median 182 days) vs EURO (median 128 days) pts (p = 0.04); there was no difference in CB pts (BMT Ind. - BMT EURO pt median 118 vs non-EURO pt median 108 days, p = 0.42). During the pandemic, as compared with EURO pts BMT delays were further exacerbated in non-EURO pts (Ind. - Consult median 13 &amp; Ind. - BMT median 33 days). Conclusions: Few older non-EURO pts are allografted. Matched SIB &amp; 8/8 mURD transplants predominantly serve EURO pts; the majority of non-EURO pts receive HLA-disparate grafts. Older age &amp; non-EURO ancestry are associated with delayed BMT. CB transplants (CBT) are the fastest regardless of ancestry. Finally, the pandemic further exacerbated delays for non-EURO pts. Strategies to mitigate referral barriers (esp. for older non-EURO pts), prompt adult donor evaluations, efficient URD searches, &amp; utilization of all alternative donors are critical to ensure timely BMT for all. Given the rapid availability, CBT should have high priority in high-risk or urgent pts &amp; speedy graft procurement can compensate for late referral. [Table: see text]
Health care resource utilization (HCRU) and costs in patients with biliary tract cancer (BTC) treated with systemic therapy in the United States (US).
Authors: Liya Wang, Mukul Singhal, Madhulika Eluri, Adriana Valderrama, Bal Nepal, Shital Kamble, Michael Grabner, Usha Malhotra, Abby B. Siegel, Shilpi Swami, Milind M. Javle
Journal: Journal of Clinical Oncology (2022)

4090 Background: BTC is associated with poor prognosis and limited treatment choices. There is limited evidence on HCRU and costs among BTC patients receiving systemic treatments (ST). This study examined HCRU and total direct cost of care among BTC patients treated with ST to understand the disease burden in management of BTC. Methods: A retrospective cohort study of BTC patients who received first line (1L) ST was conducted, using US private payer Cancer Care Quality Program data and administrative claims from the HealthCore Integrated Research Database between 07/01/2014 - 03/31/2021. Patients with ampullary cancer, brain/ CNS metastases, other primary cancer before BTC diagnosis were excluded. Per patient per month (PPPM) costs in 2020 USD were calculated during 1L, 2L, and 3L treatments associated with HCRU from inpatient, emergency room, and outpatient visits as well as outpatient pharmacy dispensing. Results: Among 298 BTC patients (biliary tract, n=203; gallbladder, n=65; bile duct, n=30; stage IV, n=231; stage III, n=28; stage I/II, n=39) who received ST, mean (SD) age was 61.7 (9) years at 1L treatment initiation, and the majority were female (58%). Following 1L treatment, 44% received 2L treatment, and 16% received 3L treatment. Median follow-up was 7.6 months. Among 201 (67%) patients who had hospitalization in the follow-up period, mean (SD) number of hospitalizations was 2.5 (2), and the average length of stay was 7.0 (5) days. Total PPPM all-cause costs were the lowest during 1L treatment (mean [SD]: $19,589 [$22,603]), and increased as the treatment advanced (2L: $22,617[$19,302]; 3L: $33,534[$40,588]). Similar trend was observed in BTC-related total costs with $16,237 ($22,452) in 1L, $19,083 ($18,670) in 2L and $27,609 ($39,949) in 3L. The table summarizes BTC-related HCRU and PPPM cost during each line of therapy. Conclusions: Study findings suggest significant resource use burden and high total direct medical costs for BTC patients receiving ST. Hospitalizations and outpatient visits represent important HCRU and cost for BTC. These data indicate a need for future newer innovative therapies in the management of BTC.[Table: see text]